Silencing of YAP attenuates pericyte‐myofibroblast transition and subretinal fibrosis in experimental model of choroidal neovascularization

Xu, Ya-Hui; Feng, Yifan; Zou, Rong; Yuan, Fangyan; Yuan, Yuanzhi

doi:10.1002/cbin.11809

Cited by 11 publications

(8 citation statements)

References 71 publications

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“…In our previous bioinformatics analysis, 27 DEGs were highly enriched in the MAPK signaling pathway, including MAPK9, MAPK11, MAPK13, MAPK14, MAPK8IP1 and MAPK8IP2 (data not shown). Some studies have demonstrated that the MAPK signaling pathway may participate in neural or cardiovascular pericyte differentiation [ 67 – 69 ], but whether the TGF-β1/MAPK pathway participates in renal pericyte metabolism and differentiation needs further study.…”

Section: Discussionmentioning

confidence: 99%

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

Chen

Deng

et al. 2023

J Transl Med

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Background Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes. Methods Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration. Results An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition. Conclusions The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.

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Section: Discussionmentioning

confidence: 99%

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

Chen

Deng

et al. 2023

J Transl Med

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“…The underlying mechanisms of subretinal fibrosis secondary to nAMD are complicated and remain incompletely elucidated. Extensive literature corroborated the involvement of additional factors, such as pericyte-myofibroblast transition (PMT) [ 53 ], EndMT [ 54 ], activated microglia [ 55 ], macrophages [ 56 ] and Müller glia [ 57 ] in the laser-induced CNV mouse model, which contribute to the accumulation of differentiated myofibroblasts and deposition of ECM, ultimately leading to fibrosis formation in nAMD. Therefore, the contribution of Wnt5a or Wnt/β-catenin in the MT of other cell types during subretinal fibrosis remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration

Liu,

Du,

Xie

et al. 2024

J Neuroinflammation

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Background Neovascular age-related macular degeneration (nAMD), accounts for up to 90% of AMD-associated vision loss, ultimately resulting in the formation of fibrotic scar in the macular region. The pathogenesis of subretinal fibrosis in nAMD involves the process of epithelial–mesenchymal transition (EMT) occurring in retinal pigment epithelium (RPE). Here, we aim to investigate the underlying mechanisms involved in the Wnt signaling during the EMT of RPE cells and in the pathological process of subretinal fibrosis secondary to nAMD. Methods In vivo, the induction of subretinal fibrosis was performed in male C57BL/6J mice through laser photocoagulation. Either FH535 (a β-catenin inhibitor) or Box5 (a Wnt5a inhibitor) was intravitreally administered on the same day or 14 days following laser induction. The RPE-Bruch's membrane-choriocapillaris complex (RBCC) tissues were collected and subjected to Western blot analysis and immunofluorescence to examine fibrovascular and Wnt-related markers. In vitro, transforming growth factor beta 1 (TGFβ1)-treated ARPE-19 cells were co-incubated with or without FH535, Foxy-5 (a Wnt5a-mimicking peptide), Box5, or Wnt5a shRNA, respectively. The changes in EMT- and Wnt-related signaling molecules, as well as cell functions were assessed using qRT-PCR, nuclear-cytoplasmic fractionation assay, Western blot, immunofluorescence, scratch assay or transwell migration assay. The cell viability of ARPE-19 cells was determined using Cell Counting Kit (CCK)-8. Results The in vivo analysis demonstrated Wnt5a/ROR1, but not Wnt3a, was upregulated in the RBCCs of the laser-induced CNV mice compared to the normal control group. Intravitreal injection of FH535 effectively reduced Wnt5a protein expression. Both FH535 and Box5 effectively attenuated subretinal fibrosis and EMT, as well as the activation of β-catenin in laser-induced CNV mice, as evidenced by the significant reduction in areas positive for fibronectin, alpha-smooth muscle actin (α-SMA), collagen I, and active β-catenin labeling. In vitro, Wnt5a/ROR1, active β-catenin, and some other Wnt signaling molecules were upregulated in the TGFβ1-induced EMT cell model using ARPE-19 cells. Co-treatment with FH535, Box5, or Wnt5a shRNA markedly suppressed the activation of Wnt5a, nuclear translocation of active β-catenin, as well as the EMT in TGFβ1-treated ARPE-19 cells. Conversely, treatment with Foxy-5 independently resulted in the activation of abovementioned molecules and subsequent induction of EMT in ARPE-19 cells. Conclusions Our study reveals a reciprocal activation between Wnt5a and β-catenin to mediate EMT as a pivotal driver of subretinal fibrosis in nAMD. This positive feedback loop provides valuable insights into potential therapeutic strategies to treat subretinal fibrosis in nAMD patients.

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“…Additionally, YAP is connected to the mitogen‐activated protein kinase (MAPK)/ERK pathway, participates in pericyte‐myofibroblast transition and promotes CNV fibrosis 24 . In a laser‐induced CNV mouse model, YAP knockdown not only reduced the proliferation, migration and differentiation of human retinal microvascular pericytes but also attenuated pericyte‐myofibroblast transformation and subretinal fibrosis 24 . These findings highlight the role of the Hippo pathway in AMD, and identify YAP/TAZ as possible targets for preventing AMD‐related neovascularization and subretinal fibrosis.…”

Section: Hippo Signalling Pathway In Eye Diseasesmentioning

confidence: 99%

“…Recent studies have demonstrated that pharmacological inhibition or genetic depletion of YAP attenuates hypoxia‐ or TGF‐β2‐induced inflammation and EndMT in HUVECs, and reverses laser‐induced subretinal fibrotic changes in mouse models, providing a new therapeutic target for the treatment of subretinal fibrosis in wet AMD 75,86,87 . Additionally, YAP is connected to the mitogen‐activated protein kinase (MAPK)/ERK pathway, participates in pericyte‐myofibroblast transition and promotes CNV fibrosis 24 . In a laser‐induced CNV mouse model, YAP knockdown not only reduced the proliferation, migration and differentiation of human retinal microvascular pericytes but also attenuated pericyte‐myofibroblast transformation and subretinal fibrosis 24 .…”

Section: Hippo Signalling Pathway In Eye Diseasesmentioning

confidence: 99%

“…20 In addition, Fossdal et al identified a point mutation in TEAD1 (Y421H) that affected the interaction between TEAD1 and YAP, resulting in Sveinsson chorioretinal atrophy, a hereditary ocular disease. 21 Numerous studies have also revealed that this cascade has a significant impact on several eye conditions including cataracts, 22 diabetic retinopathy (DR), 23 age-related macular degeneration (AMD), 24 proliferative vitreoretinopathy (PVR), 25 retinoblastoma (RB) 26 and uveal melanoma (UM). 27 In this review, recent advances in the association between the Hippo pathway centered on YAP/TAZ, the ocular system and common ocular diseases are outlined (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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The Hippo signalling pathway and its impact on eye diseases

2024

J Cellular Molecular Medi

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The Hippo signalling pathway, an evolutionarily conserved kinase cascade, has been shown to be crucial for cell fate determination, homeostasis and tissue regeneration. Recent experimental and clinical studies have demonstrated that the Hippo signalling pathway is involved in the pathophysiology of ocular diseases. This article provides the first systematic review of studies on the regulatory and functional roles of mammalian Hippo signalling systems in eye diseases. More comprehensive studies on this pathway are required for a better understanding of the pathophysiology of eye diseases and the development of effective therapies.

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Silencing of YAP attenuates pericyte‐myofibroblast transition and subretinal fibrosis in experimental model of choroidal neovascularization

Cited by 11 publications

References 71 publications

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII

Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration

The Hippo signalling pathway and its impact on eye diseases

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